The present invention relates to a furocoumarin for the photochemotherapy of psoriasis and of other skin diseases sensitive to this treatment, such skin diseases characterized by cellular hyperproliferation or by lack of skin pigmentation.
The furocoumarins, widely diffused in the vegetable world, are well-known. They can be subdivided into two general groups: psoralens, or linear furocoumarins, and angelicins, or angular furocoumarins. A singular characterizing property of linear and angular furocoumarins is represented by their photosensitizing activity, which is evidenced on different biological substrata; such activity, as is known, obtained by the combined action of the furocoumarin and long-wave ultraviolet light (UV-A).
The linear furocumarins (psoralens) are well known for their cutaneous photosensitizing activity. If, for example, the skin of a human or that of a guinea-pig is treated first with linear furocoumarins and successively irradiated with long wave ultraviolet light (UV-A), after a period of about 12-14 hours a cutaneous erythema appears and is followed by a dark pigmentation after some days. This property has already been exploited since 1948 by El Mofty employing a natural psoralen, xantotoxin (8-methoxypsoralen) which is extracted from an Egyptian plant, the Ammi Majus, for the treatment of leucodermin or vitiligo. See A. M. El Mofty, "Vitiligo and psoralens", edited by A, M. El Mofty, Pergamon Press, Oxford, 1968. The cure of this skin disease, which is characterized by the presence on the skin of white spots which do not resume their natural pigmentation even if exposed to the sunlight, is effected by treating these spots with a psoralen and successive exposure to UV-A light; this treatment restores the pigmentation.
More recently psoralens have been employed in the photochemotherapy of psoriasis, and of other skin diseases characterized by hyperproliferation of the cutaneous cells, either by oral or topical application. See H. Tronnier et al, "About The Current Status of Methoxsalen UV-A-Therapy in Dermatology", Casteliania 2,267(1974) and J. A. Parrish et al; "Photochemotherapy Of Psoriasis With Oral Methoxsalen and Longwave Ultraviolet Light", N. Eng. J. Med. 291,1207 (1974).
The oral route of administration is simpler than topical application; it permits a better check of the skin-photo-toxicity and an easy control of the skin pigmentation, which gives perfectly homogenous results. Balanced against it, oral administration can produce a possible hepatoxicity; see H. Tronnier et al, Photochemotherapy In Dermatology, in "Photochemotherapy: Basic Technique and Side Effects", Proceedings of the German-Swedish Symposium on Photomedicine in Oberursel (W. Germany) p. 71, Apr. 23-25, 1975, edited by E. G. Jung, Schattauer Veriag, Stuttgart-New York, (1976) and E. Wolff: Report on Round Table, Photochemotherapy (PUVA) of Psoriasis, in "Research on Photobiology", edited by A. Castellani, Proceedings of the VI Int. Congress of Photocology, Rome Aug. 29-Sept. 3, 1976, p. 751, Plenum Press, New York, 1977. Additionally a certain risk of cataract has been reported, in that the psoralens accumulate in the lenses of the eye, which are exposed to the action of the sun light; see S. Lerman et al "A Method For Detecting 8-methoxypsoralen In The Ocular Lens", Science 197, 1287 (1977).
On the other hand the topical application of psoralens appears less simple and more dangerous for other reasons, in that the checking of the phototoxic effect on the skin becomes more difficult. This is because the non-homogenous distribution of the substance causes a less homogenous pigmentation and, moreover, renders a higher risk of skin cancer. See T. B. Fitzpatrick: Discussion, in "Photochemotherapy: Basic Technique and Side Effects", Proceedings of the German-Swedish Symposium on Photomedicine in Oberursel (W. Germany) Apr. 23-25, 1975, p. 120, Supra; G. Rodighiero; "The Problem Of The Carcinogenic Risk By Furocoumarins", Prog.biochem. Pharmacol. 14, 94 (1978); J. H. Epstein, "Risk and Benefits Of The Treatment of Psoriasis", N. Eng. J. Med. 300, 852 (1979); R. S. Stern et al "Risk of Cutaneous Carcinoma In Patients Treated with Oral Methoxsalen Photochemotherapy For Psoriasis", N. Eng. J. Med. 300, 852 (1979).
In spite of these disadvantages, however, photochemotherapy using psoralens in the present state is the treatment of choice and preferable to other less efficacious and more dangerous forms of therapy, among them, for example, the use of only radiation in the form of short wave length ultraviolet (UV-B) light, the use of drugs that are typically regarded as anti-tumor agents or of topical preparations having a coal tar base.
In any case, independently of the type of administration, the basic concept of photochemotherapy consists in exploiting the characteristic properties of the psoralens to inhibit the DNA and RNA synthesis and in cellular reproduction. In the psoralens, nevertheless, these inhibitive properties are closely connected with phototoxic properties which are manifested on the skin by the formation of erythema and successive hyperpigmentation. Up to now it has been very difficult with psoralens to dissociate the desired therapeutic activity from any untoward phototoxic effects.
It is also known that angelicin, that is angular furocoumarin, while it is capable of inhibiting the synthesis of the nucleic acids and arresting cellular division, does not provoke either erythema or hyperpigmentation on the skin. See F. Bordin, et al, "Studies on The Photosensitizing Properties of Angelicin: Contribution of Monofunctional Adducts Furocoumarin-DNA To The Production of The Photosensitized Effects," Ital. J. Biochem, 24, 258 (1975) and M. A. Pathak et al, Bioassay of Natural and Synthetic Furocoumarin (psoralens), J. Inv. Dermatol, 32, 509 (1959). Nevertheless, the photobiological activity of angelicin is very weak, in fact so weak as to be practically not exploitable in therapy, because of its low capacity of photobinding to DNA; see G. Rodighiero et al, Mechanism of Skin Photosensitization By Furocoumarins: Photoreactivity of Various Furocoumarins With Native DNA and with Ribosomal RNA, Biochem. Biophys. Acta 217, 40 (1970).
In the following Table I properties of some of the known linear furocoumarins or psoralens, i.e. 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5',8-trimethylpsoralen (TMP) are compared with the properties of non-linear furocoumarin or angelicin.
TABLE I ______________________________________ Properties of known furocoumarins Non- linear furo- Linear Furocoumarins coumarin Property (8-MOP, 5-MOP, TMP) (Angelicin) ______________________________________ Photosensitizing activity known, strong known, absent Stimulation of melamin strong, well known absent, not pigmentation well inves- tigated, unknown Carcinogenicity known, unknown, strong (topical) (topical weak (oral) and oral) Mutagenicity known, strong known, weak DNA intercalation property strong and well evident and known known DNA synthesis inhibiting known, strong known, property weak Photobinding capacity known, strong known, to DNA weak Monoadduct forming known, strong known, property weak Interstrand cross-linking strong, well known absent, and induction in DNA known Therapeutic effectiveness known, good to unknown in Vitiligo excellent and not in- vestigated Therapeutic effectiveness known, good to unknown in psoriasis excellent and not in- vestigated Therapeutic effectiveness known, unknown in other diseases ______________________________________